Sodium ibuprofen is an effective pain killer, and one of the advantages associated with it is the fact that it is easily absorbed through the lining of the stomach and can thus easily be taken in oral doses. According to the published literature, solid dosage forms made from sodium ibuprofen are superior in pharmaceutical kinetics (i.e., they enter and peak in the blood stream more rapidly than other solid dosage forms of ibuprofen). In fact, it is thought that sodium ibuprofen may be more effective in smaller amounts than its hydrogen substituted analog, ibuprofen, due to this ease of absorption.
Sodium ibuprofen is easily prepared as a powder. However, despite intensive research in the field, it remains difficult to prepare solid dosage forms from sodium ibuprofen using conventional approaches. One of the difficulties is that sodium ibuprofen dihydrate has poor flowability characteristics and thus tends to cake readily even when blended with conventional anti-caking agents such as colloidal silica or talc. The poor flow characteristics of sodium ibuprofen dihydrate, even though formulated with flow improvers, can result in erratic weight variations in the solid dosage forms such as tablets and caplets being produced.
Furthermore, sodium ibuprofen is unpalatable, having a taste that is difficult to mask; and when it is compressed into tablets, such tablets resist disintegration into the component powder, once swallowed, until reaching the stomach. Therefore, such tablets must be small enough such that they can easily transit as a whole down the esophagus.
A primary challenge in formulating sodium ibuprofen for easy dosing is the strong tendency for it to stick to the punch used to compress it into tablets, forming a film on the punch surface. It has been found that despite the use of lubricants, formulations high in sodium ibuprofen, including many of those of the present invention, are prone to sticking to punch surfaces. This film coating that is formed on the punch surface is undesirable from several standpoints. From an aesthetic standpoint, the coating on the punch reduces the “shine” of the tablets formed on that punch. From a practical perspective, the coating on the punch surface results in what is known as sticking, picking, and capping. A further disadvantage is that the punches must be cleaned of the accumulated sodium ibuprofen formulation or the aesthetic and dosage discrepancy can increase with time. However, cleaning the punch generally requires that the tableting operation temporarily be shut down, resulting in equipment downtime which inevitably increases the cost per unit.
One technique for reducing such sticking, is to reduce the proportion of sodium ibuprofen in the tablet, while maintaining the dosage amount at the same level. However, doing so can lead to tablets that are unacceptably large because in order to get the same amount of ibuprofen in a single tablet, the tablet must be increased in size in order to accommodate increased amounts of inert excipient.
While ibuprofen can be tableted, without sticking, with a wide variety of punching surfaces at a wide variety of tablet concentrations and dosages, sodium ibuprofen formulations have been observed to stick to most punch surfaces. In particular, formulations that are sufficiently high in active to give tablets of effective dose and easily swallowed size, have been observed to stick to some degree to nearly all types of punch surfaces.
Chemical differences between ibuprofen and its sodium salt analog are generally invoked by those of skill in the art to explain the difference in sticking properties. Ibuprofen is a racemic compound—methods of preparation generally give two enantiomers, and a single unit cell crystal of crystalline ibuprofen will contain one molecule of each enantiomer. However, sodium ibuprofen is a racemic conglomerate, i.e., it is generally characterized by an equal molar physical mixture of the individual enantiomeric crystals, such that only one enantiomer is present in each crystal and in each unit cell of the crystal lattice.
In the presence of water and some common excipients, the racemic conglomerate structural arrangement is distorted during wet granulation. As a result of the structure distortion, the heat of phase transition, which is normally at about 100° C., is greatly reduced leading to fragile crystals and structurally weak granules. Without desiring to be bound by theory, it is believed that the coating of the punch surface with sodium ibuprofen during tablet formation may occur due to a weak crystal structure caused by the above-mentioned crystal structure distortion a result of the changes in crystals. Thus, it has been thought by those of skill in the art that the propensity of sodium ibuprofen to stick to surfaces that ibuprofen did not stick to is a consequence of the chemical differences between the two compounds.
The above-described propensity for sticking, combined with the higher molecular weight of sodium ibuprofen dihydrate (264 g/mol) with respect to ibuprofen (which means that oral dose tablets must contain a greater wt % active than would be required of tablets of ibuprofen 206 g/mol)), has contributed to the under use of sodium ibuprofen despite its therapeutic advantages.
It would therefore be of considerable advantage if a way could be provided for forming sodium ibuprofen compositions capable of being more readily converted into solid dosage form such as tablets or caplets using conventional rotary press tableting equipment without encountering the various difficulties referred to above. It would also be of considerable advantage if a way could be provided for producing highly flowable granules from sodium ibuprofen dihydrate so that the dosage level of hard shell capsules filled with the granules can be kept more uniform. Furthermore, there exists a need for a tableting method, which produces acceptably-sized, reliably-dosed and aesthetically-acceptable sodium ibuprofen tablets.
This invention addresses all of the foregoing needs in an effective manner.